Distinct roles of IL-18 and IL-1β in murine model of macrophage activation syndrome

Mao Mizuta; Natsumi Inoue; Masaki Shimizu; Naoto Sakumura; Tadafumi Yokoyama; Rie Kuroda; Yasuhiro Ikawa; Naotoshi Sugimoto; Kenichi Harada; Akihiro Yachie; Taizo Wada

doi:10.1016/j.jaci.2023.05.027

Distinct roles of IL-18 and IL-1β in murine model of macrophage activation syndrome

J Allergy Clin Immunol. 2023 Oct;152(4):940-948.e6. doi: 10.1016/j.jaci.2023.05.027. Epub 2023 Jun 22.

Authors

Affiliations

¹ Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
² Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: mshimizu.ped@tmd.ac.jp.
³ Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Faculty of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
⁴ Department of Human Pathology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
⁵ Division of Patient Safety, Kanazawa University Hospital, Kanazawa, Japan.

PMID: 37352976
DOI: 10.1016/j.jaci.2023.05.027

Abstract

Background: IL-18 and IL-1β play a central role in the pathogenesis of systemic juvenile idiopathic arthritis and its life-threatening complication, macrophage activation syndrome (MAS).

Objectives: This study aimed to clarify the role of IL-18 and IL-1β in the pathogenesis of MAS.

Methods: We developed a mouse model to evaluate the role of each cytokine with Toll-like receptor 9 stimulation after continuous infusion with IL-18, IL-1β, and a combination of both for 7 days. The symptoms and laboratory findings were compared among the IL-18, IL-1β, and combination (IL-18+IL-1β) groups.

Results: Body weight was significantly decreased in the IL-1β and combination groups. Splenomegaly was observed in all groups, whereas hepatomegaly was noted in the IL-18 group only. Decreased T-cell numbers, anemia, and thrombocytopenia were observed in the combination group. IFN-γ, CXCL9, and IL-12A mRNA levels were upregulated and IL-10 mRNA levels in the spleen were downregulated in the IL-18 group. Hepatomegaly and splenomegaly in the IL-18 group were observed in a dose-dependent manner. TNF-α, CXCL9, and IL-12A mRNA levels were upregulated only in those mice with extremely elevated plasma IL-18 levels.

Conclusion: IL-18 and IL-1β have distinct roles in the pathogenesis of MAS. Dual blockade of IL-18 and IL-1β might be necessary to treat MAS.

Keywords: IL-18; IL-1β; Macrophage activation syndrome; systemic juvenile idiopathic arthritis.